Antigen-specific T lymphocyte activation occurs through the clonally distributed T cell receptor. The available set of AlphaBeta T cell receptors is dictated by both positive and negative intrathymic selection events. Tbe molecular basis of this selection, in particular, how bias for self-MHC presented peptides is achieved without corresponding deletions of these clones during establishment of self-tolerance, is unknown. Furthermore, the quantitative and qualitative relationships between receptor occupancy and signaling for differentiation, whether in the thymus or of mature T cells in the periphery, is also poorly understood. This project uses cellular and molecular tools to study the development of the T cell repertoire and the activation of T cells upon ligand engagement of AlphaBeta and non-clonal surface receptors. Co-stimulatory events regulate IL-2 production by CD8 and CD4 T cells. We have demonstrated that the anergic state previously described for Th1 CD4+ T cells also exists from CD8 cytotoxic cells, and can be dissociated from receptor signalling for lytic function. Investigation of a prototypic Th1-type T cell clone specific for cytochrome c and EalphaEBetak unexpectedly revealed that addition of the known peptide ligand recognized by this cell interfered with alloantigen stimulation of IL-2 production by the clone. This inhibition does not appear to be due to simple competition for creation of the alloantigen itself or to over-stimulation of the clone. Rather, it seem that peptide complexes with the mutant class II molecule leads to low affinity (or low efficacy) occupancy of receptors, which interferes with intracellular signaling mediated by the alloantigen-TCR pair. Preliminary data suggest an interference with induction of co-stimulatory activity in the antigen presenting cell. These observations, if they can be generalized and better understood, suggest a previously unappreciated role of low affinity T cell receptor recognition events in regulation of T cell differentiation and activation. This may provide an important clue to the control of thymic selection, as well as the initiation of immune responses. These findings also point to a new approach for the control of autoimmune diseases characterized by oligoclonal T cell responses.